No modulatory effect of neurokinin-1 receptor antagonists on serotonin uptake in human and rat brain synaptosomes

Lieb, Klaus; Fiebich, Bernd L.; Herpfer, Inga; Mantovani, M.; Löffler, Marlene; Feuerstein, Thomas J.

doi:10.1016/j.euroneuro.2005.04.013

Cited by 9 publications

(3 citation statements)

References 29 publications

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“…Moreover, the effects of NK-1r antagonists on serotonin neurons in the dorsal raphe are thought to be indirect (perhaps via alterations in noradrenergic activity) because NK-1rs on these neurons are virtually absent (Conley et al, 2002); thus, the effects of NK-1r on dorsal raphe neurons are likely the result of actions in other brain regions and/or effects on other neurotransmitter systems. Additionally, there are some noteworthy differences between the actions of NK-1r antagonists and standard antidepressants—namely that their efficacy is not achieved by altering activity at reuptake sites (Adell, 2004; Conley et al, 2002; Kramer et al, 1998; Lieb et al, 2005; Maubach et al, 2002). Partially in response to this knowledge, novel drugs have been developed that have dual action in blocking both NK-1rs and serotonin reuptake (Ryckmans et al, 2002).…”

Section: Emotion Stress and Diseases Of Chronic Inflammationmentioning

confidence: 99%

Substance P at the nexus of mind and body in chronic inflammation and affective disorders.

Rosenkranz

2007

Psychological Bulletin

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For decades, research has demonstrated that chronic diseases characterized by dysregulation of inflammation are particularly susceptible to exacerbation by stress and emotion. Likewise, rates of depression and anxiety are overrepresented in individuals suffering from chronic inflammatory disease. In recent years, substance P has been implicated in both the pathophysiology of inflammatory disease and the pathophysiology of depression and anxiety by 2 parallel fields of study. This review integrates the literature from these 2 parallel fields and examines the possibility that substance P dysregulation may be a point of convergence underlying the overlap of chronic inflammatory disease and mood and anxiety disorders. First, the involvement of substance P in peripheral inflammation and in the immune events associated with chronic inflammatory disease is discussed, with a focus on inflammatory bowel disease and asthma. Next, the function of substance P in the communication of peripheral inflammation to the brain is considered. Finally, to complete the bidirectional loop of brain-immune interactions, substance P expression in anxiety and depression as well as its potential role in the neural regulation of peripheral inflammation is reviewed.

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Section: Emotion Stress and Diseases Of Chronic Inflammationmentioning

confidence: 99%

Substance P at the nexus of mind and body in chronic inflammation and affective disorders.

Rosenkranz

2007

Psychological Bulletin

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“…Thus, further investigation is necessary to clarify these discrepancies. The increased extracellular 5-HT efflux by NK1R antagonism is likely caused by interaction with release mechanisms rather than by interfering with 5-HT reuptake or degradation because neither 5-HT transporters nor monoamine oxidase activity is modulated by different NK1R antagonists (Conley et al, 2002;David et al, 2004;Lieb et al, 2005). To determine the functional sites for septal SP/5-HT interactions, we used immunofluorescence and immunoelectron microscopy for precise cellular and subcellular localization of NK1Rs in rat LS.…”

Section: Behaviorally Significant Interaction Between Sp and 5-ht Sysmentioning

confidence: 99%

Neurokinin 1 Receptor Antagonism Promotes Active Stress Coping Via Enhanced Septal 5-HT Transmission

Ebner

Singewald

Whittle

et al. 2007

Neuropsychopharmacol

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Antagonists of the substance P (SP) preferring neurokinin 1 receptor (NK1R) represent a promising novel class of drugs for the treatment of stress-related disorders such as depression and anxiety disorders; however, the involved neuronal pathways releasing SP in response to stressors are ill defined. By using in vivo microdialysis in combination with a highly sensitive and selective radioimmunoassay we found that exposure to forced swim stress increased SP release in the rat lateral septum (LS), a key area in processing emotions and stress responses. Acute administration of the selective NK1R antagonist L-822429 injected either systemically or locally into the LS reduced passive and facilitated active stress-coping strategies in the forced swim test. This effect seems to be mediated by enhanced intraseptal serotonergic transmission via serotonin (5-HT)1A receptors since NK1R blockade reversed the swim stress-induced decrease to an increase in extracellular 5-HT efflux, and furthermore the behavioral effects of L-822429 were blocked by intraseptal 5-HT1A receptor antagonism. A direct heterosynaptic regulation by NK1R on 5-HT release from serotonergic fibers was ruled out by immunocytochemistry at the light and electron microscopic level indicating involvement of GABAergic interneuron(s) in this interaction. Taken together, our data identify the LS as a critical brain area for the involvement of SP transmission in the modulation of stress responses and demonstrate that NK1R blockade can elicit a functionally significant facilitatory effect on 5-HT transmission, which does not necessarily involve the previously proposed interaction with neuronal firing at the cell body level of raphe neurons.

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“…Integration at the Level of the DRN: Significance of 5-HT 1A Autoreceptors .5) for 5-HT transporters (pK i values, o5.0), and do not modify the actions of SSRIs at synaptosomes in vitro (Lieb et al, 2005;Millan, MJ, unpublished observation). Antagonists at 5-HT 1B autoreceptors on serotonergic terminals enhances increases in 5-HT levels elicited by SSRIs (Gobert et al, 1997).…”

Section: Discussion Potentiation By Gr205171 Of the Influence Of Citamentioning

confidence: 99%

Neurokinin1 Antagonists Potentiate Antidepressant Properties of Serotonin Reuptake Inhibitors, Yet Blunt Their Anxiogenic Actions: A Neurochemical, Electrophysiological, and Behavioral Characterization

Gobert

Brocco

Dekeyne

et al. 2008

Neuropsychopharmacol

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Though neurokinin 1 (NK 1 ) receptor antagonists are active in experimental models of depression, clinical efficacy has proven disappointing. This encourages interest in association of NK 1 receptor blockade with inhibition of serotonin (5-HT) reuptake. The selective NK 1 antagonist, GR205171, dose-dependently enhanced citalopram-induced elevations of extracellular levels of 5-HT in frontal cortex, an action expressed stereospecifically vs its less active distomer, GR226206. Further, increases in 5-HT levels in dorsal hippocampus, basolateral amygdala, nucleus accumbens, and striatum were likewise potentiated, and GR205171 similarly facilitated the influence of fluoxetine upon levels of 5-HT, as well as dopamine and noradrenaline. In parallel electrophysiological studies, the inhibitory influence of citalopram and fluoxetine upon raphe-localized serotonergic neurones was stereospecifically blunted by GR205171. Antidepressant actions of citalopram in a forced-swim test in mice were stereospecifically potentiated by GR205171, and it also enhanced attenuation by citalopram of stress-related ultrasonic vocalizations in rats. Further, GR205171 and citalopram additively abrogated the advance in circadian rhythms provoked by exposure to light in hamsters. By contrast, GR205171 stereospecifically blocked anxiogenic actions of citalopram in social interaction procedures in rats and gerbils, and stereospecifically abolished facilitation of fearinduced foot tapping by fluoxetine in gerbils. By analogy to GR205171, a further NK 1 antagonist, RP67580, enhanced the influence of citalopram upon frontocortical levels of 5-HT and potentiated its actions in the forced swim test. In conclusion, NK 1 receptor blockade differentially modulates functional actions of SSRIs: antidepressant properties are reinforced, whereas anxiogenic effects are attenuated. Combined NK 1 receptor antagonism/5-HT reuptake inhibition may offer advantages in the management of depressed and anxious states.

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No modulatory effect of neurokinin-1 receptor antagonists on serotonin uptake in human and rat brain synaptosomes

Cited by 9 publications

References 29 publications

Substance P at the nexus of mind and body in chronic inflammation and affective disorders.

Substance P at the nexus of mind and body in chronic inflammation and affective disorders.

Neurokinin 1 Receptor Antagonism Promotes Active Stress Coping Via Enhanced Septal 5-HT Transmission

Neurokinin1 Antagonists Potentiate Antidepressant Properties of Serotonin Reuptake Inhibitors, Yet Blunt Their Anxiogenic Actions: A Neurochemical, Electrophysiological, and Behavioral Characterization

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